Antibiotic-resistant Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB) are a serious and growing problem in the treatment of both hospital-acquired and community infections. New parenteral agents (e.g. glycopeptides, lipopetides and beta-lactams (BLs)) active against resistant GPB, including MRSA, have been and are being developed, however none of these are both bactericidal and orally bioavailable. The only orally bioavailable agent active vs. MRSA is linezolid, which is bacteriostatic. In an effort to address these unmet healthcare needs, Blanca Pharmaceuticals has advanced, over the past three years, two new bactericidal carbacephem antibiotics (BP-101 and BP-102) as parenteral agents with excellent activity against antibiotic-resistant GPB, and intrinsic activity against a broad range of GNB. Preliminary data show that, when combined with a beta-lactamase inhibitor (BLI), these two compounds are highly active against many strains (ESBLs) resistant to 3rd-generation cephalosporins. These carbacephems have the advantage of greater chemical and metabolic stability when compared to similar cephems, resulting in moderate oral bioavailability (8% for BP-101 and 3% for BP-102, respectively, in rats). Hypothesis: Prodrugs of BP-101 and BP-102 can increase their oral bioavailability to clinically useful levels (~50%). Blanca has initiated the synthesis of prodrugs of BP-101, and expects to test the oral bioavailability of the first three compounds in the 4th Qtr of 2007. The three aims of this grant are to: 1. Continue to explore the feasibility of the synthesis of prodrugs of BP-101 and BP-102. 2. Prepare a larger number of prodrugs of BP-101 of several different types and then apply this information to the synthesis of a smaller number of prodrugs of BP-102, which may have a different solubility profile resulting in better absorption as a prodrug. All proposed prodrugs will mask the carboxylic acid group at position-4 of the carbacephems, but functional groups on the side-chain at position-7 will also be pro-drugged, as a means of modifying solubility, stability or charge characteristics. 3. Evaluate prodrugs of BP-101 and BP-102, in a series of in vitro and in vivo assays, to determine if any has sufficient bioavailability (~25 to 50%) to advance, in a Phase II application, to evaluation in primates or other non-rodent models of oral bioavailability. PUBLIC HEALTH RELEVANCE: Infections caused by antibiotic-resistant Gram-positive and Gram-negative bacteria are an increasing healthcare problem. This application seeks to develop orally bioavailable, bactericidal, carbacephems active against methicillin-resistant Staphylococcus, penicillin-resistant Streptococcus and Gram-negative bacteria including, when combined with an existing beta-lactamase inhibitor such as potassium clavulanate, Acinetobacter, Enterobacteriaceae and Pseudomonas resistant to 3rd-generation cephalosporins. [unreadable] [unreadable] [unreadable]